Immunization, Vaccines and Biologicals

Tuberculosis vaccine development

To reach the new End TB goals of a 95% reduction in TB deaths and a 90% reduction in TB cases by 2035, a comprehensive approach is needed that includes new and more effective vaccines, as well as improved diagnostics and treatment. The currently used Bacille Calmette-Guérin (BCG) vaccine was developed in 1921 and remains the only available vaccine against TB. Unfortunately, BCG is only partially effective: it provides some protection against severe forms of pediatric TB, but is not completely protective against disease in infants and is unreliable against adult pulmonary TB. Disease in latently infected adults and adolescents accounts for most of the disease burden, and transmission, worldwide. There is therefore an urgent need for new, safe and effective vaccines that prevent against all forms of TB, including drug-resistant strains, in all age groups, including those with HIV.

Due to the complex nature of Mycobacterium tuberculosis (Mtb) and its pathology within the human host, multiple vaccine development strategies are being pursued:

  • Prevention of infection: vaccines that can be given prior to Mtb exposure, in order to prevent initial infection and therefore disease
  • Prevention of disease: vaccines that can be administered after exposure to Mtb, to people who are infected but may be asymptomatic and at risk of developing disease in the future. This type of vaccine would protect against manifestation of active disease and therefore reduce transmission.
  • Prevention of recurrence: vaccines that can be administered after infection and treatment of Mtb disease, to prevent reactivation and subsequent transmission

Priming TB vaccines, such as the current BCG, are administered to newborns as part of the expanded programme for immunization and, since its first use in 1921, BCG has become the most widely administered vaccine in history with approximately 4 billion doses administered worldwide. However, there is no substantial evidence that BCG reduces the risk of becoming infected with Mtb, but vaccination does prevent severe disease in infants and children. Unfortunately, it is not possible to ‘boost’ the protection offered by initial BCG vaccination with a subsequent BCG shot later in life. An alternative strategy to offer protection beyond infancy and early childhood is needed.

Broadly speaking, current TB vaccine candidates are designed to be either:

  • A better prime vaccine to replace BCG with a vaccine that is more efficacious for a longer period of time, and may that prevent TB infection as well as disease in infants who have not been infected with Mtb.
  • A booster vaccine, most likely delivered during adolescence to prevent infection and/or progression to active disease for those who are latently infected, as BCG immunity wanes.

In addition, an immunotherapeutic vaccine is being developed for individuals with active TB in conjunction with TB drug therapy, with the aim of shortening the duration of the therapy and/or reducing recurrence rates after completion of treatment.

Sixteen different TB vaccine candidates are currently in clinical trials, with a handful approaching or currently in proof-of concept (Phase IIb) studies in the field, and many more in preclinical development. These vaccine candidates include five which are based on whole cell mycobacteria, and the remainder are various sub-unit based approaches in which Mtb antigens are expressed as recombinant proteins that are either formulated with adjuvants or presented in recombinant viral vectors.

The major stumbling blocks in TB vaccine development to date have been the lack of an immunological correlate of protection, the reality that protection in preclinical challenge models does not reflect field efficacy data, and, in this context, the need for a human challenge model to help rationalise selection of candidates to proceed to efficacy studies. Continued research in these areas is critical to facilitate and de-risk vaccine product development and is proceeding in parallel to advancing candidates in the clinic.

Last updated: 12 May 2015